Abstract: The era of the genome promised that human genetics would quickly translate into personalized medicine. Genome-wide association studies on large samples from human populations have indicated that main effects of common polymorphisms or rare variants are unlikely to lead to improved ability to predict disease risk and therapeutic response. Epistasis (gene-gene interaction) and pleiotropy (diverse effects of the same gene) are known to play major roles in the genetic architecture of complex traits in model organisms, but have not yet been explored in human biology. This project aims to overcome the current challenge in human genetics in an innovative way by studying autism traits in congenital disorders of the Ras-MAPK pathway. Autism is a complex heritable disorder affecting nearly 1% of the population, and like most complex genetic disorders, the heritability is unaccounted for by current models of genetic association. Ras-MAPK diseases are genetic disorders with known mutations that include effects on craniofacial, cardiac, cutaneous, musculoskeletal and ocular development, as well as carrying increased risk of cancer and varying expression of neurocognitive impairment. Our preliminary data shows that these disorders are strongly associated with autism and that common polymorphisms in the same genes are associated with idiopathic familial autism. Therefore, Ras-MAPK pathway disorders provide an ideal model by which to explore epistasis and pleiotropy in the complex trait of autism. We will ascertain subjects with Ras-MAPK disorders, measure autism-related traits, and perform genome-wide mapping for interactors with the known Ras-MAPK genes. We will then establish induced pluripotent stem cell models from fibroblasts of patients with these disorders in order to investigate expression and functional assays utilizing cells differentiated into varying fates. This project has great translational potential not only for understanding how genetic variants mediate disease risk, but also with immediate implications for treatment approaches. Public Health Relevance: Autism Spectrum Disorders have recently been estimated to affect nearly 1% of Americans, and can cause severe disability to individuals and families across the lifespan with extremely limited treatment options. With better understanding of the genetic architecture of autism and causes of common co-morbidities, diagnosis, prognosis, prevention and treatment options could be improved. This project could lead the way to translating genetics into medicine for other common complex genetic disorders.